The Power of Neuroactive Steroids

Click here to watch the companion YouTube video for this series.

In this series of three articles, I have sought to (1) provide an introductory guide to the power of neuroactive steroids, to (2) describe the dangers of the drug finasteride with particular respect to its effect on neuroactive steroids, and to (3) provide some preliminary ideas on how the reader may protect himself from these effects.

The first article in the series is the most difficult to get through. Expecting no background knowledge from readers, I have tried to provide as complete a picture of the biochemistry of neuroactive steroids as would be required to properly grasp the effect of finasteride. While difficult to get through, I encourage the reader to push through it, as the information is valuable for both the finasteride user and the modern biohacker.

While I have focused on 5a-reductase dependent sex and neurosteroids, I have also reviewed other steroids that have powerful neurological effects. I have only excluded two relevant steroids, testosterone and estrogen, because they are beyond the scope of this series. If you would like to learn about the cognitive and behavioral impacts of testosterone and estrogen, be sure to ask me about them on the next Instagram Q&A post.

With these disclaimers in place, let’s discuss neuroactive steroids.


Our bodies produce steroids from sterols, including cholesterol, in three separate places: the adrenals, the gonads, and the brain. Cholesterol is metabolized through a cascade of desmolases, hydroxylases, dehydrogenases, reductases, aromatase, and conjugation enzymes, into biologically active steroids. A neuroactive steroid is a steroid that affects neurotransmitter receptors in the brain, in addition to its effect on the testosterone, progesterone, and estrogen receptors in the brain. The effect on a neurotransmitter will produce a direct response from the brain, while the sex hormone receptor will produce a chronic effect, altering gene expression in the body. Classically, a neurosteroid[1] is distinguished from a broadly neuroactive steroid by not having a communicative role at sex hormone receptors, though this turns out to be an oversimplification.

In this review, we will ignore the cognitive and behavioral effects of testosterone, dihydrotestosterone, and estrogens. We will be concerned with a precursor to testosterone in the hormone cascade, DHEA, as well as its sulfated form, and to the metabolites of testosterone, androstanediol and androsterone. We will also be concerned with the progenitor to all steroids, pregnenolone, and with the poorly understood neurosteroid THDOC. Finally, we will pay particularly close attention to the progestogens, which are progesterone and its metabolites allopregnanolone, and, to a lesser degree, isopregnanolone.

It is important to understand that all of the aforementioned steroids are in large part produced in the adrenals during stress. In that sense, they are part of the hypothalamic-pituitary-adrenal (HPA) adaptive stress response of the human. For this reason, interfering with their production can be thought of as changing our bodies’ stress response. Nonetheless, with the exception of THDOC, they are also produced directly in the brain.


Through intermediates, progesterone is synthesized from cholesterol during the luteal phase of a woman’s menstrual cycle, in the ovaries. During pregnancy, it is synthesized mainly by the placenta. During periods of stress, it is synthesized by the adrenal glands under the control of adrenocorticotropic hormone. While in women, systemic progesterone is derived both of the ovaries and the adrenals, in men systemic progesterone originates entirely from the adrenals.

Though progesterone freely crosses the blood-brain barrier, progesterone is also a neurosteroid, synthesized in the brain both by neurons and glial cells. Cholesterol is also neurosteroid. 25% of the body’s cholesterol is in the brain, and it is synthesized locally in the brain by glial cells, as cholesterol cannot bypass the blood-brain or blood-nerve barriers.

To synthesize neurosteroids in the brain, cholesterol must be transported across the mitochondrial membrane. This occurs through a molecular complex formed by 4 members: the translocator protein 18 kDa (TSPO), the steroidogenic acute regulatory protein (StAR), the voltage-dependent anion channel protein (VDAC), and the adenine nucleotide transporter protein (ANT). The rate-limiting step is TSPO[2]. Once in the mitochondria, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (p450scc). After cholesterol is converted into pregnenolone, the enzyme 3b-hydroxysteroid dehydrogenase (3BHSD) produces progesterone in the cytoplasm or mitochondria. Progesterone is then metabolized by the type 1 5a-reductase enzyme, that finasteride targets, into dihydroprogesterone (DHP). DHP is then metabolized by the 3a-hydroxysteroid oxidoreductase (3AHSOR) into allopregnanolone or by 3b-hydroxysteroid oxidoreductase (3BHSOR) into isopregnanolone.

Because the activity of 3AHSOR is greater than 5AR, 5AR is the rate-limiting step in the synthesis of neurosteroids in the brain. Also, note that there are three isoforms of the 5a-reductase enzyme (5ARs). Type 1 5ARs are abundantly expressed in the hypothalamus, hippocampus, cerebellum, and cerebral cortex. The type 2 isoform is almost undetectable in the adult human brain[3], though it is widespread in the body. Finasteride and dutasteride both inhibit the type 2 and type 3 isoforms. Finasteride partially inhibits the type 1 isoform, while dutasteride inhibits it fully. This means that finasteride will reduce DHP, allopregnanolone, and isopregnanolone, while dutasteride will almost entirely prevent their synthesis.

From pregnenolone’s other metabolite 11-deoxycorticosterone (DOC), dihydrodeoxycorticosterone (DHDOC) is produced through the 5AR enzymes. DHDOC is then metabolized by the 3a-hydroxysteroid dehydrogenase (3BHSD) enzyme into the neurosteroid tetrahydrodeoxycorticosterone (THDOC). Unlike allopregnanolone, THDOC is not present in the brain after adrenalectomy and gonadectomy, and thus appears not to be synthesized in the brain[4]. It is produced following acute stress and peaks 10-30 minutes after the stressor. As THDOC is highly lipophilic, like the other neurosteroids, it readily passes the blood-brain barrier[5].

While progesterone and DOC are made directly from pregnenolone, testosterone is produced indirectly through the cascade, from either dehydroepiandrosterone (DHEA) through the same 3BHSD enzyme that converted pregnenolone into progesterone, or from androstenedione. In the brain, testosterone is then converted into dihydrotestosterone (DHT) by the type 1 5AR, and DHT is further converted into 3a-androstanediol (androstanediol) through the same 3AHSOR enzyme that converted DHP into allopregnanolone. Androstanediol is then converted by the 17b-hydroxysteroid dehydrogenase enzyme into androstenedione. (Note that androstanediol’s 3b-androstanediol isomer is not a neurosteroid – in this series, androstanediol refers to the 3a isomer only).

Having briefly reviewed the metabolisms of the neuroactive steroids pregnenolone, DHEA, allopregnanolone, isopregnanolone, THDOC, androstanediol, we shall next characterize their effects in the brain. Note that pregnenolone and DHEA are both actively converted into sulfated forms by the enzyme steroid sulfatase, and that the sulfated forms have different effects on cognition and behavior.


Recall that neurosteroids have an acute effect on brain neurotransmitter receptors and a chronic effect on gene transcription through their weaker effect[6] at the sex hormone receptors of androgen, progesterone, and estrogen. The focus of much of the direct effect of neurosteroids is the inhibitory GABAA receptor[7]. While allopregnanolone, THDOC, androstanediol, and androsterone potentiate or allosterically modulate the GABAA receptor, pregnenolone sulfate[8] and DHEA sulfate produce a biphasic action at the GABAA receptor and enhance the excitatory glutamatergic NMDA receptor function[9]. Another progesterone metabolite, isopregnanolone, also acts antagonistically at the GABAA receptor. Broadly, allopregnanolone, THDOC, androstanediol, and androstenedione are inhibitory neurosteroids while pregnanolone sulfate, DHEA sulfate, and isopregnanolone are excitatory. Note that androstanediol and androsterone potentiate GABAA with less potency[10] than allopregnanolone and THDOC. Consequently, allopregnanolone and THDOC are considered the most powerful neurosteroids.

When the GABAA receptor is in the presence of the neurosteroids allopregnanolone, THDOC, androstanediol and androstenedione, there is an enhanced probability of the receptor chloride channel being open, such that the average time of the channel being open increases and the closed time decreases, resulting in an inhibition of neuronal excitation. Unlike benzodiazepines, which agonize only GABAA receptors that contains g2 subunits and do not contains a2 or a6 subunits, neurosteroids modulate most GABAA receptors, including recombinant versions[11]. GABAA receptors that contain a d subunit are the most sensitive to neurosteroids[12], and transgenic mice lacking the d subunit show reduced sensitivity to neurosteroids[13]. Interestingly, GABAA receptors that contain the d subunit have less potential to be desensitized and are usually located extrasynaptically.

Though neurosteroids allosterically modulate the GABAA receptors, at pharmacologic concentrations north of 10 micromolar, they can directly agonize the receptors, even in the absence of the neurotransmitter GABA[14]. In this action, neurosteroids resemble barbiturates but not benzodiazepines[15].

The sulfated versions of pregnenolone and DHEA, which are found abundantly in the brain, reduce the frequency at which the GABAA channel open[16] when found at physiologic doses. At the nanomolar or high micromolar concentrations of pharmacologic doses, they become potent allosteric agonists[17], increasing the frequency of the channel opening and the total duration of channel opening. Nonetheless, in normal physiology, allopregnanolone, THDOC, androstanediol, and androstenedione positively modulate the receptor, while pregnenolone sulfate and DHEA sulfate (as well as isopregnanolone) negatively modulate the receptor.